James C. Grotta

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials

Summary Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35–2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95–1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01–7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11–10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98–12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99–1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Combined Intravenous and Intra-Arterial r-TPA Versus Intra-Arterial Therapy of Acute Ischemic Stroke: Emergency Management of Stroke (EMS) Bridging Trial

BACKGROUND AND PURPOSE The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms. METHODS This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety. RESULTS Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient. CONCLUSIONS This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques.

Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator

BackgroundArterial reocclusion has not been systematically studied despite the fact that 13% of patients in the National Institute of Neurological Diseases and Stroke rt-PA Trial deteriorated following initial improvement, suggesting that reocclusion might be responsible for poor clinical outcome in some of these patients. Methods Consecutive stroke patients treated with IV tissue plasminogen activator (TPA) within 3 hours and an M1 or M2 middle cerebral artery (MCA) occlusion on pre-TPA transcranial Doppler (TCD) were monitored up to 2 hours after TPA bolus. Reocclusion was defined as the Thrombolysis in Brain Ischemia flow decrease by ≥1 grades and no hemorrhage on repeat CT. The NIH Stroke Scale (NIHSS) and modified Rankin Scores (mRS) were obtained by a neurologist independently of TCD. ResultsSixty patients with median prebolus NIHSS score of 16 (range 6 to 28, 90% with ≥10 points) had TPA bolus at 130 ± 32 minutes (median 120 minutes, 58% within the first 2 hours). Recanalization was complete in 18 (30%), partial in 29 (48%), and none in 13 (22%) patients. Reocclusion occurred in 34% of patients with any initial recanalization (16/47): in 4 of 16 patients with complete recanalization (22%), and in 12 of 29 patients with partial recanalization (41%). Reocclusion was detected in four patients (25%) before TPA bolus, in three (19%) by 30 minutes after bolus, in three (19%) by the end of infusion, and in six (37%) by 60 to 120 minutes. Before reocclusion, those patients had earlier median timing of recanalization: 130 versus 180 minutes after stroke onset compared with those who recanalized without reocclusion (p = 0.01). Median prebolus NIHSS score in the reocclusion group was 13.5 versus 17 (rest, NS), whereas at 2 and 24 hours, their NIHSS scores were higher: 14 versus 9 and 16 versus 6 points (p ≤ 0.04). Deterioration followed by improvement by ≥4 NIHSS points occurred in 8 of 16 (50%) patients with reocclusion versus 10% (rest) (p < 0.05). In-hospital mortality was 25 versus 3% (p < 0.0001). At 3 months, good outcome (mRS score of 0 to 1) was achieved by 8% of patients with no recanalization, by 33% of patients with reocclusion, and by 50% of patients with stable recanalization (p ≤ 0.05), and mortality was 42% with no early recanalization, 33% after reocclusion, and 8% in patients with stable recanalization (p ≤ 0.05). ConclusionsEarly reocclusion occurs in 34% of TPA-treated patients with any initial recanalization, accounting for two-thirds of deteriorations following improvement. Reocclusion occurs more often in patients with earlier and partial recanalization, leading to neurologic deterioration and higher in-hospital mortality. However, patients with reocclusion have better long-term outcomes than patients without any early recanalization.

Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator–Related Intracerebral Hemorrhage in Acute Ischemic Stroke

BACKGROUND AND PURPOSE Five pretreatment variables (P<0.1 univariate analysis), including serum glucose (>300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated <3 hours from onset with intravenous rtPA at 2 institutions to evaluate the role of these variables in predicting ICH. METHODS Baseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. RESULTS Symptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1. 08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis. CONCLUSIONS Serum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.

High Rate of Complete Recanalization and Dramatic Clinical Recovery During tPA Infusion When Continuously Monitored With 2-MHz Transcranial Doppler Monitoring

Background and Purpose—Clot dissolution with tissue plasminogen activator (tPA) can lead to early clinical recovery after stroke. Transcranial Doppler (TCD) with low MHz frequency can determine arterial occlusion and monitor recanalization and may potentiate thrombolysis. Methods—Stroke patients receiving intravenous tPA were monitored during infusion with portable TCD (Multigon 500M; DWL MultiDop-T) and headframe (Marc series; Spencer Technologies). Residual flow signals were obtained from the clot location identified by TCD. National Institutes of Health Stroke Scale (NIHSS) scores were obtained before and after tPA infusion. Results—Forty patients were studied (mean age 70±16 years, baseline NIHSS score 18.6±6.2, tPA bolus at 132±54 minutes from symptom onset). TCD monitoring started at 125±52 minutes and continued for the duration of tPA infusion. The middle cerebral artery was occluded in 30 patients, the internal carotid artery was occluded in 11 patients, the basilar artery was occluded in 3 patien...

Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Timing of Recanalization After Tissue Plasminogen Activator Therapy Determined by Transcranial Doppler Correlates With Clinical Recovery From Ischemic Stroke

BACKGROUND The duration of cerebral blood flow impairment correlates with irreversibility of brain damage in animal models of cerebral ischemia. Our aim was to correlate clinical recovery from stroke with the timing of arterial recanalization after therapy with intravenous tissue plasminogen activator (tPA). METHODS Patients with symptoms of cerebral ischemia were treated with 0.9 mg/kg tPA IV within 3 hours after stroke onset (standard protocol) or with 0.6 mg/kg at 3 to 6 hours (an experimental institutional review board-approved protocol). National Institutes of Health Stroke Scale (NIHSS) scores were obtained before treatment, at the end of tPA infusion, and at 24 hours; Rankin Scores were obtained at long-term follow-up. Transcranial Doppler (TCD) was used to locate arterial occlusion before tPA and to monitor recanalization (Marc head frame, Spencer Technologies; Multigon 500M, DWL MultiDop-T). Recanalization on TCD was determined according to previously developed criteria. RESULTS Forty patients were studied (age 70+/-16 years, baseline NIHSS score 18.6+/-6.2). A tPA bolus was administered at 132+/-54 minutes from symptom onset. Recanalization on TCD was found at the mean time of 251+/-171 minutes after stroke onset: complete recanalization occurred in 12 (30%) patients and partial recanalization occurred in 16 (40%) patients (maximum observation time 360 minutes). Recanalization occurred within 60 minutes of tPA bolus in 75% of patients who recanalized. The timing of recanalization inversely correlated with early improvement in the NIHSS scores within the next hour (polynomial curve, third order r(2)=0.429, P<0.01) as well as at 24 hours. Complete recanalization was common in patients who had follow-up Rankin Scores if 0 to 1 (P=0.006). No patients had early complete recovery if an occlusion persisted for >300 minutes. CONCLUSIONS The timing of arterial recanalization after tPA therapy as determined with TCD correlates with clinical recovery from stroke and demonstrates a 300-minute window to achieve early complete recovery. These data parallel findings in animal models of cerebral ischemia and confirm the relevance of these models in the prediction of response to reperfusion therapy.

Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) Final Results

Background and Purpose— Induced hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke. Methods— Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33°C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not. Results– In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator. Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT). Baseline demographics and risk factors were similar between groups. Mean age was 65.5±12.1 years and baseline National Institutes of Health Stroke Scale score was 14.0±5.0; 32 (55%) were male. Cooling was achieved in all patients except 2 in whom there were technical difficulties. The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4). At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant). Symptomatic intracranial hemorrhage occurred in 4 patients (68); all were treated with tissue plasminogen activator <3 hours (1 received hypothermia). Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant). Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (P=0.001). The pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (P=0.32). Conclusion— This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke.

15d-Prostaglandin J2 Activates Peroxisome Proliferator-Activated Receptor-γ, Promotes Expression of Catalase, and Reduces Inflammation, Behavioral Dysfunction, and Neuronal Loss after Intracerebral Hemorrhage in Rats:

Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates the expression of various gene products that are essential in lipid and glucose metabolism, as well as that of the peroxisome-enriched antioxidant enzyme, catalase. Activation of PPARγ is linked to anti-inflammatory activities and is beneficial for cardiovascular diseases. However, little is known about its role in intracerebral hemorrhage (ICH). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) acts as a physiologic agonist for PPARγ. In this study, we found that injection of 15d-PGJ2 into the locus of striatal hematoma increased PPARγ-deoxyribonucleic acid (DNA) binding activity and the expression of catalase messenger ribonucleic acid (mRNA) and protein in the perihemorrhagic area. Additionally, 15d-PGJ2 significantly reduced nuclear factor-κB (NF-κB) activation and prevented neutrophil infiltration measured by myeloperoxidase (MPO) immunoassay, and also reduced cell apoptosis measured by terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL). In addition, 15d-PGJ2 reduced behavioral dysfunction produced by the ICH. Altogether, our findings indicate that injection of 15d-PGJ2 at the onset of ICH is associated with activation of PPARγ and elevation of catalase expression, suppression of NF-κB activity, and restricted neutrophil infiltration. All these events predicted reduced behavioral deficit and neuronal damage.

Transcranial Doppler Ultrasound Criteria for Recanalization After Thrombolysis for Middle Cerebral Artery Stroke

BACKGROUND AND PURPOSE Transcranial Doppler (TCD) can demonstrate arterial occlusion and subsequent recanalization in acute ischemic stroke patients treated with intravenous tissue plasminogen activator (tPA). Limited data exist to assess the accuracy of recanalization by TCD criteria. METHODS In patients with acute middle cerebral artery (MCA) occlusion treated with intravenous tPA, we compared posttreatment TCD with angiography (digital subtraction or magnetic resonance). On TCD, complete occlusion was defined by absent or minimal signals, partial occlusion by blunted or dampened signals, and recanalization by normal or stenotic signals. Angiography was evaluated with the Thrombolysis In Myocardial Ischemia (TIMI) grading scale. RESULTS Twenty-five patients were studied (age 61+/-18 years, 16 men and 9 women). TCD was performed at 12+/-16 hours and angiography at 41+/-57 hours after stroke onset, with 52% of studies performed within 3 hours of each other. Recanalization on TCD had the following accuracy parameters compared with angiography: sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, and negative predictive value (NPV) 93%. To predict partial occlusion (TIMI grade II), TCD had sensitivity of 100%, specificity of 76%, PPV of 44%, and NPV of 100%. TCD predicted the presence of complete occlusion on angiography (TIMI grade 0 or I) with sensitivity of 50%, specificity of 100%, PPV of 100%, and NPV of 75%. TCD flow signals correlated with angiographic patency (chi(2)=24.2, P<0.001). CONCLUSIONS Complete MCA recanalization on TCD accurately predicts angiographic findings. Although a return to normal flow dynamics on TCD was associated with complete angiographic resumption of flow, partial signal improvement on TCD corresponded with persistent occlusion on angiography.